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Cells in mucus from lungs of high-risk patients can predict tumor development

16.03.2006

In a group of high-risk patients, a test that examined DNA from cells expelled in sputum for evidence of "silenced" genes correctly identified the majority of patients who were later diagnosed with lung cancer, say researchers in a study published in the March 15 issue of Cancer Research.

As such, the sputum test potentially represents a unique, non-invasive, and cost-effective screening method that could lead to earlier treatment of lung cancer.

"Short of repeatedly X-raying a persons lungs to look for emerging tumors, there is no way now to screen people at high risk for lung cancer, much less predict who will be diagnosed with the cancer at a later date," said the studys senior author, Steven Belinsky, Ph.D., director of the Lung Cancer Program at the Lovelace Respiratory Research Institute in Albuquerque, N.M.

"When perfected and validated, this kind of test holds great promise for identifying people with lung cancer early enough to successfully treat them," he said.

The test was able to predict which patients would develop lung cancer up to 18 months later. Catching lung tumors within that short timeframe can change a patients outcome, Belinsky said, because these cells often proliferate rapidly after a long slow-growth period.

"Because most people are diagnosed when their cancer is advanced, they may not benefit from surgery, chemotherapy or radiation, which is why median survival from diagnosis is only 13 months," he said. "But lung tumors that can be surgically removed are associated with a five year survival rate of more than 60 percent."

The researchers are now working to perfect the test because it is not yet accurate enough for the clinic. It identified 65 percent of individuals who later developed symptoms of lung cancer, but also tagged 35 percent of cancer-free control participants.

"Our hope is that our continuing research will identify additional genes that will make a sputum test like this highly predictive," Belinsky said.

The test is also unique because it examines cells sloughed off in sputum for evidence that genes have been "turned off," in contrast to the more traditional "biomarker" assays that look for increased gene activity.

Belinsky and his research team developed the test by identifying genes known to be "hypermethylated" in lung cancer -- that is, decorated with molecules known as methyl groups that function to turn a gene off. Stephen Baylin, M.D., and James Herman, M.D., from Johns Hopkins Kimmel Cancer Center, Baltimore, Md. -- who are co-authors of this study -- are recognized leaders in this area of research.

Addition of these methyl groups to the DNA base cytosine modifies histone proteins, which act like spools around which DNA winds itself. Histones play a role in gene regulation, and when altered, prevent genes from being transcribed into proteins, according to Belinsky.

These modifications to a genes promoter region offer scientists a biomarker to determine which genes have been hypermethylated, and a panel of such markers can form an assay, he said. This assay uses stretches of artificial DNA that can attach only to specific methylated genes.

In this study, Belinsky worked with researchers at University of Colorado Health Sciences Center, Denver, Colo., to develop a blinded and nested case-control study within their Sputum Screening Cohort Study, which has been ongoing since 1993. The Colorado researchers asked whether mucus that coats all parts of the lung can contain genetic evidence of cancer cells when expelled in sputum. Their study enrolled patients who all had a history of smoking and chronic obstructive pulmonary disease. Belinsky and the researchers examined sputum from 98 people who developed cancer, and compared these samples to 92 participants who did not.

They looked at silencing of 14 genes known to be inactivated at different stages of lung cancer development, and found that six of these genes served to predict who would develop lung cancer. These genes are P16, PAX5-beta, MGMT, DAPK, GATA5, RASSF1A. Then, they found that participants who had three or more of these methylated, silenced genes in sputum, collected within 18 months of diagnosis, had a 6.5-fold increase risk for lung cancer.

The test didnt work well if the sputum was collected more than 18 months before lung cancer was diagnosed, Belinsky said. "The prevalence for methylation of gene promoters increased as the time to lung cancer diagnosis decreased," he said.

A person who tests positive for the test would receive a follow-up diagnostic bronchoscopy or X-ray to determine if tumors exist, Belinsky said. If tumors are not evident, patients could be retested in several months.

He added that the test might also be used in the future to help guide drug therapy. A new class of therapeutic drugs is being developed that are designed to reduce methylation in genes and restore their function, Belinsky explained. "When a number of these agents come on the market, then an improved sputum test could be used to match these agents to genes individual patients have lost," he said. "We can then use this kind of test diagnostically."

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